Hindawi Publishing Corporation

Neural Plasticity
Volume 2016, Article ID 1320423, 18 pages
http://dx.doi.org/10.1155/2016/1320423

Review Article
Natural Product-Derived Treatments for
Attention-Deficit/Hyperactivity Disorder: Safety, Efficacy, and
Therapeutic Potential of Combination Therapy

James Ahn,1 Hyung Seok Ahn,2 Jae Hoon Cheong,3 and Ike dela Peña1
1
Department of Pharmaceutical and Administrative Sciences, Loma Linda University, Loma Linda, CA 92350, USA
2
School of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea
3
Department of Pharmacy, Sahmyook University, Seoul 139-742, Republic of Korea

Correspondence should be addressed to Ike dela Peña; idelapena@llu.edu

Received 9 November 2015; Revised 30 December 2015; Accepted 10 January 2016

Academic Editor: Daniel Fung

Copyright © 2016 James Ahn et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological (behavioral/psychosocial)
and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of
pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and
nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical
studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also
discussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHD
treatments) may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural
product-derived ADHD interventions. Nevertheless, these treatments were considered as a “safer” approach than conventional
ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and
safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining
botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are
also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored
when used as standalone treatment or when combined with other conventional ADHD treatments.

1. Introduction interventions or a combination of both [5]. A prominent non-

Attention-deficit/hyperactivity disorder (ADHD), a neu-
rodevelopmental disorder characterized by the core symp-
toms of hyperactivity, inattentiveness, and impulsivity [1], is
currently regarded as the most common neuropsychiatric
disorder among children [2]. Furthermore, while this disor-
der is most often diagnosed during childhood, it may also
affect an individual throughout life [3]. It is crucial to develop
efficacious treatments for ADHD, given its serious academic,
social, and familial consequences, along with the risk of
incurring comorbid conditions and later substance abuse [4].
A number of treatment strategies have been suggested
for ADHD since its recognition as a specific disorder in the
1970s. Presently, typical treatment plans utilize a nonphar-
macological (behavioral/psychosocial) and pharmacological
pharmacological intervention in ADHD is behavioral ther-
apy (behavior modification), which showed promise espe-
cially in youth and young adult ADHD patients. In principle,
behavioral therapy operates via rewarding desired behaviors
with positive reinforcement and discouraging problematic
behaviors by introducing limits and consequences [6, 7].
Another type of behavior modification focuses on social
skills training which is conducted in a group setting, where
participants are taught by a therapist or qualified teacher
appropriate/acceptable social behaviors which they (patients)
are then encouraged to practice and repeat [7, 8]. Other
approaches to ADHD therapy include memory training
that employs computer software (Cogmed), neurofeedback,
electroencephalography biofeedback, green space, medita-
tion, yoga, exercise, and acupuncture in order to achieve
2 Neural Plasticity
symptom management (for reviews see [9–11]). However, as
these therapies are not widely available, only a few patients
can benefit from these treatment approaches. Although they
are easy to implement, the need for time and professional
therapists and also the involvement of not only the patient but
also members of the family and teachers during the course
of behavioral therapy limit the use of behavioral ADHD
therapies.
ADHD has been associated with abnormalities in cat-
echolaminergic function in the brain [12]. The use of
medications that increase levels of catecholamine in the
brain received widespread support as these drugs have
been demonstrated to alleviate ADHD symptoms [12].
Drugs indicated in the management of ADHD are classified
as stimulant and nonstimulant medications [13, 14]. The
predominantly used or prescribed pharmacological inter-
ventions for ADHD are stimulant medications [13, 14].
Methylphenidate and dextroamphetamine are examples of
these drugs, which are structurally similar to endogenous
catecholamines and whose activity increases extracellular
dopamine and norepinephrine levels, thereby correcting
the underlying abnormalities in catecholaminergic functions
and restoring neurotransmitter imbalance [12]. Nonstimulant
alternatives include atomoxetine and norepinephrine spe-
cific reuptake inhibitors and the antidepressants bupropion,
imipramine, and phenelzine [15, 16]. Nonstimulant alterna-
tives have also been reported to increase catecholamine levels
in the brain resulting in behavioral improvement. However,
nonstimulant medications have been found to be inferior to
stimulant treatments on efficacy endpoints [13, 16, 17].
While pharmacological treatments generally improve
ADHD symptoms for most children, 20–30% of affected
individuals are nonresponders or are unable to tolerate
adverse side effects of these drugs [11, 18]. Some of the side
effects of stimulant medications include headache, insomnia,
and decreased appetite, motor tics, nausea, and abdominal
pain [5, 15, 18]. Concerns over long-term exposure risks also
discourage parents to medicate their children with stimulant
drugs [17]. Furthermore, the high likelihood for dependence,
diversion, and abuse, particular to drugs classified as schedule
II (i.e., stimulants), limits the use of stimulant medications,
as ADHD has been also associated with increased risk of
substance use disorder [17].
Due to concerns over the safety and efficacy of cur-
rent pharmacological ADHD interventions, there has been
growing interest in the development of alternative treatments
such as natural product-derived ADHD treatments including
botanical or herbal medicines, vitamins, minerals, and amino
acids [9–11]. These alternative treatments are appealing to
parents who desire for more “natural” interventions for their
children [9, 10]. Approximately 50% of parents of ADHD
children used these treatments alone or in combination with
other drugs or substances [19–22]. In this study, we provide
a descriptive review of natural product-derived ADHD treat-
ments including complementary ADHD interventions such
as vitamins, minerals, and other nutritional supplements,
report findings of clinical trials which evaluated efficacy
and safety of these interventions and discuss the poten-
tial mechanism(s) by which these agents improve ADHD
symptoms. The botanical agents are enumerated in Table 1,
and Table 2 summarizes the vitamins, minerals, and other
nutritional supplements evaluated for ADHD treatment.
Furthermore, we also discuss the findings of studies which
evaluated safety and efficacy of combining botanical agents
or pharmacological ADHD treatments to treat ADHD. These
information are summarized in Table 3.
2. Methods
Searches were made in the electronic databases PubMed,
PyschINFO, and The Cochrane Library for English language
articles from 2001 up to December 1, 2015. PubMed was
used to search ADHD search terms in combination with
particular natural product-derived treatments. The search
strategy employed included combining these keywords: “nat-
ural products,” “plant”, “vitamins,” “minerals,” “essential
fatty acids,” “amino acids”, “combination natural prod-
ucts,” or “combination with methylphenidate” and “ADHD”
or “attention-deficit/hyperactivity disorder.” This process
yielded 671 papers covering a wide range of research article
types. As we were interested only in natural product-derived
ADHD treatments which were evaluated in clinical trials, we
concentrated on open-label, randomized controlled trials, as
well as observational studies. Moreover, the inclusion crite-
ria included samples consisting of children and adolescent
ADHD patients (below 18 years of age), as well as sample
size ≥ 10. The number of English language articles that were
reviewed for this paper was 30.
3. Results
3.1. Pycnogenol® (French Maritime Pine Bark Extract). Pyc-
nogenol is a standardized extract derived from the bark of
the French maritime pine (Pinus pinaster). This extract is
rich in catechin, phenolic acids, procyanidins, and taxifolin,
each with multiple biologic effects [30, 31]. Several studies
on Pycnogenol showed its potentiality in improving ADHD
symptoms in patients. Most notably, a double-blind, placebo-
controlled trial with 61 participants (ages 6–14 years) reported
that Pycnogenol treatment (1 mg/kg/day) for 1 month alle-
viated ADHD symptoms, particularly episodic hyperactivity
and inattentiveness, and improved visual-motor coordina-
tion [30]. One month after termination of Pycnogenol, there
was a relapse of symptoms in ADHD participants. The latter
study also assumed that Pycnogenol’s therapeutic benefits
were mediated via an increase in nitric oxide production,
which modulates dopamine and norepinephrine release and
intake [30]. Pycnogenol reportedly produced mild side effects
such as gastric discomfort. Nevertheless, the relatively small
number of participants treated with Pycnogenol and the short
duration of the study limit the generalization of the study’s
findings. It is noteworthy, however, that significant effects
of Pycnogenol were observed, coupled with minimal side
effects, supporting the suggestion that it could be used as an
alternative ADHD treatment [30].
Another randomized, placebo-controlled study inves-
tigating efficacy of Pycnogenol reported improvement in
attention along with reduction in oxidative DNA damage
 Table 1: Clinical trials evaluating safety and efficacy of botanical agents for ADHD.
Neural Plasticity

Proposed mechanism of Comments (side effects,

Study Botanical agent Method Participants Outcomes
action etc.)
Bacopa (Bacopa monnieri) Reduction of ADHD
Neuroprotection,
Standardized Bacopa symptoms (restlessness, Safe and well tolerated
31 children, 6–12 years regulation of dopamine,
Dave et al. [23] monnieri extract (SBME) Open-label study poor self-control, Mild gastrointestinal
old with ADHD and inhibition of
(225 mg/day), for 6 inattention, impulsivity, side effects
cholinesterase
months etc.)
Ginkgo biloba
Uebel-von Very low rates of mild
Ginkgo (EGb 761®), Improvement of ADHD
Sandersleben et al. Open clinical pilot study 20 children with ADHD Improvement in adverse events during
240 mg daily, given for 3 core symptoms
[24] cerebrovascular blood observational period
to 5 weeks
flow, reversal of 5-HT1,
Ginkgo biloba
50 children, 6–14 years and noradrenergic
Ginkgo biloba Lesser side effects
Randomized, old with ADHD Improvement of ADHD receptor reductions
(80–120 mg/day) or (headache, insomnia,
Salehi et al. [25] double-blind controlled (𝑛 = 25 Ginkgo biloba symptoms. Less effective Reverse inhibition of
methylphenidate and loss of appetite) than
trial versus 𝑛 = 25 than methylphenidate MAO-A and MAO-B
(20–30 mg/day), for 6 methylphenidate
methylphenidate)
weeks
Ginseng
Korean red ginseng
18 children, 6–14 years Improvement in Taste aversion and
Lee et al. [26] (1,000 mg b.i.d.) and Observational study Nootropic effect on CNS
old with ADHD attention repulsion to ginseng
placebo twice a day for 8 Increased dopamine and
weeks norepinephrine levels
Improvement of Neuroprotective effects
Ginseng
70 children, 6–15 years hyperactivity and
Korean red ginseng Randomized,
old with ADHD (𝑛 = 33 inattention symptoms No reported adverse
Ko et al. [27] extract (1 g KRG double-blind, placebo-
KRG versus 𝑛 = 37 Decreased quantitative events/side effects
extract/pouch) twice a day controlled trial
placebo) electroencephalography
for 8 weeks
theta/beta ratio
Randomized,
Ningdong 72 children, 6–13 years
double-blind, Similar efficacy to Regulation of dopamine
Ningdong (5 mg/kg/day) old with ADHD (𝑛 = 36
Li et al. [28] methylphenidate- control by increasing HVA Hypersomnia
versus methylphenidate Ningdong versus 𝑛 = 36
controlled (methylphenidate) concentration in the sera
(1 mg/kg/day), for 8 weeks methylphenidate)
trial
Double-blind,
Decreased appetite and
randomized,
Akhondzadeh et al. Passion flower Improvement of ADHD anxiety/nervousness
methylphenidate- 34 children with ADHD Not specified
[29] Passiflora incarnata symptoms compared with
controlled clinical
methylphenidate group
trial
3
 4

Table 1: Continued.
Proposed mechanism of Comments (side effects,
Study Botanical agent Method Participants Outcomes
action etc.)
Influence on
Attenuation of catecholamine formation
Pycnogenol 61 children, 6–14 years hyperactivity and or metabolism
Randomized, Mild side effects
Trebatická et al. Pycnogenol (1 mg/kg/day) old with ADHD (𝑛 = 44 improvement of Increased production of
double-blind, including slowness and
[30] or placebo treatment for 4 Pycnogenol, versus attention, visual-motoric nitric oxide which
placebo-controlled study gastric discomfort
weeks 𝑛 = 17 placebo) coordination, and modulates dopamine
concentration and norepinephrine
release and intake
61 outpatient children,
Pycnogenol
Randomized, 6–14 years old with Improved attention,
Chovanová et al. Pycnogenol (1 mg/kg/day) No reported adverse
double-blind, ADHD (𝑛 = unspecified reduction in oxidative Antioxidant properties
[31] or placebo treatment for 4 events/side effects
placebo-controlled study Pycnogenol versus damage
weeks
placebo)
56 children, 6–17 years
Randomized, No significant
old with ADHD (𝑛 = 27 No reported adverse
Weber et al. [32] St. John’s wort double-blind, improvement in ADHD
SJW versus 𝑛 = 27 events/side effects
placebo-controlled study symptoms
placebo)
30 children, 5–11 years
Improvement of ADHD
old with ADHD
symptoms in VOMT or
(𝑛 = 10Valeriana Inhibition of the
3x potency group, in
Valerian (Valeriana Double-blind, placebo- officinalis mother breakdown of GABA in No reported adverse
Razlog et al. [33] comparison to placebo,
officinalis) controlled, clinical trial tincture (VOMT) or the central nervous events/side effects
in particular, inattention,
𝑛 = 10 3x potency of system
impulsivity, and/or
VOMT versus 𝑛 = 10
hyperactivity
placebo, for 3 weeks)
Neural Plasticity

Table 2: Clinical trials evaluating safety and efficacy of nutritional supplements for ADHD.
Study Supplement
Acetyl-L-carnitine (LAC)
Torrioli et al. [34] LAC (500 mg, 2 times/day)
or placebo for 12 months
Acetyl-L-carnitine (ALC)
ALC in weight-based doses
Arnold et al. [35]
from 500 to 1,500 mg b.i.d. or
placebo for 16 weeks
Essential fatty acids
Highly unsaturated fatty acid
(HUFA): EPA 186 mg/day,
DHA 480 mg/day,
Richardson and
𝛾-linolenic acid 96 mg,
Puri [36]
vitamin E 60 IU, cis-linoleic
acid 864 mg, AA 42 mg, and
thyme oil 8 mg or olive oil
(placebo), for 12 weeks
Essential fatty acids
PUFA supplement
comprised of 480 mg DHA,
80 mg EPA, 40 mg
Stevens et al. [37] arachidonic acid (AA),
96 mg GLA, and 24 mg
alpha-tocopheryl acetate or
an olive oil placebo for 4
months
Neural Plasticity
Proposed mechanism of Comments (side effects,
Method Participants Outcomes
action etc)
Modulation of neural
transmission by
51 children (ADHD and Reduction of ADHD
Randomized, increasing acetylcholine
Fragile X syndrome), symptoms versus
double-blind, placebo- synthesis, stimulating its No adverse events/side
6–13 years old (𝑛 = 24 Placebo on Clinical
controlled, parallel, release and release of effects reported
ALC versus 𝑛 = 27 Global Impressions
multicenter study dopamine in the
placebo) Parental Rating
striatum in various brain
regions
112 children, 5–12 years
Multisite parallel-group Acetyl-L-carnitine
old (𝑛 = 53 No adverse events/side
double-blind superior to placebo in
Acetyl-L-carnitine effects reported
randomized pilot trial inattentive subtype
versus 𝑛 = 59 placebo)
41 children, 9
Attenuation of ADHD
participants withdrew Influence on signal
symptoms, for example,
Randomized, before the end of transduction relevant to
inattention, Upset stomach and
double-blind, placebo- 12-week period, neuronal structure,
hyperactivity, difficulty swallowing
controlled study 8–12 years old (𝑛 = 15 development, and
improvement in
HUFA versus 𝑛 = 14 functions
cognition and emotion
placebo)
Clear benefit for all
behaviors characteristic
of ADHD was not
50 children (girls and observed Mediation of abnormal
Randomized,
boys), 𝑛 = 25 PUFA Treatment effects for neuronal signaling that
double-blind, placebo- Not specified
supplementation, 𝑛 = 25 conduct and attention as results in aberrant
controlled study
placebo well as with clinical behaviors
improvements in
oppositional/defiant
behavior
5

Study Supplement
Essential fatty acids
LC-PUFA capsules
containing 400 mg fish oil
and 100 mg evening
Sinn and Bryan primrose oil with EPA
[38] (93 mg), DHA (29 mg), GLA
(10 mg), and vitamin E
(1.8 mg) or placebo. Six
active or 6 placebo capsules
per day for 15 weeks
Essential fatty acids
LC-PUFA capsules
containing 400 mg fish oil
and 100 mg evening
primrose oil with EPA
Sinn et al. [39]
(93 mg), DHA (29 mg), GLA
(10 mg), and vitamin E
(1.8 mg) or placebo. Six
active or 6 placebo capsules
per day for 15 weeks
Essential fatty acids
2 capsules twice a day of
phosphatidylserine (PS)
Manor et al. [40] containing omega-3 (300 mg
of PS and 120 mg of EPA +
DHA) or cellulose capsules
as placebo, for 15 weeks
Essential fatty acids
EFA capsules containing
240 mg of linoleic acid (LA)
60 mg of alpha-linolenic acid
(ALA), 95 mg of mineral oil,
Raz et al. [41]
and 5 mg of a-tocopherol (as
an antioxidant) 2 times/day
or placebo: vit. C (500 mg
ascorbic acid) 2 times/day,
for 7 weeks
Table 2: Continued.
6
Proposed mechanism of Comments (side effects,
Method Participants Outcomes
action etc)
Modulation of neural
cell signaling and
neurotransmitter
132 children (data processes
available for 104 and 87 Significant treatment PUFAs with other
Randomized, children) 7–12 years old effects based on parental nutrients such as vit. C,
No adverse events/side
double-blind, crossover, (𝑛 = 36 PUFAs versus rating of core ADHD B3 , and B6 modulates
effects
placebo-controlled study 𝑛 = 41 PUFA + symptoms in both PUFA PUFA’s role in the
micronutrients versus groups versus placebo synthesis of
𝑛 = 27 placebo) prostaglandins and
chemicals important for
biological and brain
function
Phase 1: 𝑛 = 129 children
with ADHD (PUFA
versus PUFA +
multivitamins/minerals
Influence on metabolic
Randomized, one-way versus placebo for 15 Improved ability on
and neural activities Two cases of nausea and
crossover, placebo- weeks) attention control and
Increasing dopamine one episode of nose
controlled study Phase 2: 𝑛 = 104 vocabulary performance
activity in the frontal bleed
Phases 1 and 2 children with ADHD during phase 2
lobe
(PUFA, PUFA +
multivitamin/minerals,
and placebo for 15
weeks)
Maintenance of integrity
200 children (6–13 years
of cell membranes
old) randomly assigned
Influence on
to PS-omega-3 capsules Mild adverse event
Randomized, Improvement of ADHD dopaminergic and
or placebo profile: GI discomfort,
double-blind, symptoms (impulsivity, cholinergic systems
𝑁 = 162 children atopic dermatitis,
single-center, placebo- inattention, mood, and Increasing omega-3
completed 15 weeks of nausea, tics, and
controlled trial behavior issue) LC-PUFA which
treatment (𝑛 = 110PS- hyperactivity
improves behavioral,
omega-3, 𝑛 = 52
sensory, and
placebo)
neurological dysfunction
73 children, 7–13 years
Both treatments
old, 63 children
Randomized, ameliorated some Improvement in
completed the study No adverse events/side
double-blind, ADHD symptoms. No behavioral, sensory, and
(𝑛 = 39 EFA supplement effects reported
placebo-controlled trial difference in efficacy cognitive functions
versus 39 placebo
between treatments
vitamin C)
Neural Plasticity

Study Supplement
Essential fatty acids
345 mg of DHA per day
Voigt et al. [42]
(𝑛 = 32) or a placebo capsule
(𝑛 = 31) for 4 months
Essential fatty acids
DHA group: fermented
soybean milk (600 mg
DHA/125 mL, 3/week), bread
Hirayama et al. rolls (300 mg DHA/45 g,
[43] 2/week) and steamed bread
(600 mg DHA/60 g, 2/week)
or placebo foods containing
olive oil instead of DHA-rich
fish oil for 2 weeks
Iron
80 mg ferrous sulfate tablets
Konofal et al. [44]
or placebo once daily in the
morning for 12 weeks
Vitamin B6 and magnesium
ADHD children:
magnesium-vitamin B6
Mousain-Bosc et
(Mg-B6) regimen (6 mg/kg/d Open study
al. [45]
Mg, 0.6 mg/kg/d vit-B6) for
six months Controls did not
receive Mg-B6
Zinc
150 mg zinc sulfate or 150 mg
Bilici et al. [46]
sucrose (placebo) daily for 12
weeks
Table 2: Continued.
Neural Plasticity
Proposed mechanism of Comments (side effects,
Method Participants Outcomes
action etc)
54 children 6–12 years DHA supplementation
Randomized, old (𝑛 = 27 did not significantly Well tolerated and no
double-blind, placebo docosahexaenoic acid improve in any objective adverse effects were
controlled study (DHA) versus 𝑛 = 27 or subjective measure of reported
placebo) ADHD symptoms
40 children with ADHD
DHA supplementation
Randomized, 6–12 years old (𝑛 = 20 No serious side effects
did not improve
double-blind, docosahexaenoic acid were reported in the
ADHD-related
placebo-controlled study (DHA) versus 𝑛 = 20 study
symptoms
placebo)
23 ADHD children with Improvement of
Randomized, Iron is a cofactor in the Minor side effects were
low serum ferritin level hyperactive/impulsive
double-blind, synthesis of both reported, such as nausea,
(<30 ng/mL) 5–8 years and inattentive
placebo-controlled, pilot norepinephrine and constipation, and
old (𝑛 = 18 iron versus symptoms in the ADHD
trial dopamine abdominal pain
𝑛 = 5 placebo) rating scale
Vitamin B6 facilitates
the production of the
serotonin
76 children (mean age: Attenuation of
Magnesium is a
6.9 years; 13 girls and 27 hyperactivity and
nonspecific inhibitor of
boys) (40 ADHD aggressiveness School No reported side effects
calcium and NMDA
children & 36 healthy attention was also
channels
children) improved
Magnesium can
influence catecholamine
signaling
Zinc sulfate better than
Randomized, placebo in decreasing No serious side effects
400 children 6–14 years Increased zinc levels
double-blind, hyperactivity and reported. Metallic taste
old (𝑛 = 202 zinc versus necessary for cognitive
parallel-group impulsivity and was a common
𝑛 = 198 placebo) development
placebo-controlled trial improving socialization, complaint
but not inattention
7

Study Supplement
Zinc
Zinc sulfate (55 mg/day) +
methylphenidate
Akhondzadeh et al.
(1 mg/kg/day) or sucrose
[47]
(placebo) 55 mg +
methylphenidate
(1 mg/kg/day) for 6 weeks
Zinc
Zinc 1: 15 mg/day (once a
day) or Zinc 2: 30 mg/day
(twice a day) or placebo (8
weeks); amphetamine
Arnold et al. [48] 5–15 mg/daily (based on the
weight)
Duration of experiment was
13 weeks (8 weeks controlled
+ 5 weeks amphetamine
add-on)
8
Table 2: Continued.
Proposed mechanism of Comments (side effects,
Method Participants Outcomes
action etc)
Significantly greater
44 children, 5–11 years treatment effects (as per
old (𝑛 = 22 parent and teacher Zinc regulates dopamine Nausea and metallic
Randomized,
methylphenidate + zinc rating scale scores) in function indirectly, taste were common
double-blind, clinical
versus 𝑛 = 22 zinc sulfate with through its action on complaints. Overall, it
trial
methylphenidate + methylphenidate melatonin was well tolerated
placebo) treatment over placebo
with methylphenidate
Randomized, 52 children 6–14 years No appreciable
Gastrointestinal
double-blind, old (𝑛 = 20 Zinc 1 or difference between both
discomfort reported by 1
placebo-controlled, pilot 𝑛 = 8 Zinc 2 versus dosages of zinc and
patient
trial 𝑛 = 24 placebo) placebo
Neural Plasticity
 Neural Plasticity

Table 3: Clinical trials demonstrating efficacy of combination therapy of botanical agents and herbs/supplements with methylphenidate in treating ADHD.
Study Methods Participants Outcomes Comments
Five participants
Ginkgo biloba and Ginseng reported adverse events
Ginkgo biloba extract Improvement of ADHD (increased ADHD
(50 mg) plus American symptoms symptoms,
36 children, 3–17 years
Lyon et al. [49] ginseng, Panax Open, pilot study (hyperactivity, aggressiveness, sweating,
old with ADHD
quinquefolium (200 mg) impulsiveness, and headache, and
twice/day anxiety) tiredness), only 2
(combination product) considered related to the
study
Combination therapy
Jingling oral and
𝑛 = 50 ADHD children Significant improvement more effective than
methylphenidate Randomized, blinded
Wang et al. [50] with transient tic of ADHD symptoms, as methylphenidate alone
Methylphenidate study
disorder well as tics in improving ADHD
(10–40 mg/d)
and tic symptoms
Significant improvement
Randomized, in ADHD symptoms in Yizhi had fewer side
methylphenidate- 210 children with those taking effects when given alone
Ding et al. [51] Yizhi and methylphenidate
controlled hyperkinetic syndrome combination therapy or in combination than
trial compared to either given methylphenidate
as monotherapy
Side effects reported:
Improved parent and
Randomized, anxiety, loss of appetite,
44 children (26 boys, 18 teacher rating scale
Akhondzadeh et al. Zinc sulfate and double-blind, and nausea, headache,
girls), 5–11 years old with scores for those
[47] methylphenidate methylphenidate + abdominal pain,
ADHD supplemented with zinc
placebo controlled trial insomnia, and metallic
sulfate as an adjunct
taste
9
10
and normalization of homeostatic antioxidant status in
ADHD patients treated for 1 month with the compound [31].
A month after Pycnogenol treatment, the total antioxidant
status (TAS) was increased in ADHD children (ADHD
children showed lower TAS levels at the beginning of the
study compared with healthy controls) and was significantly
elevated after 1 month of termination of Pycnogenol treat-
ment. Oxidative stress is believed to be a contributing factor
to the etiology of ADHD [52]. The improvement of ADHD
symptoms in ADHD patients given Pycnogenol has been
attributed to the drug’s potent antioxidant effects [52]. Some
ancillary benefits of Pycnogenol were normalization of the
concentration of urinary catecholamines in children with
ADHD and improvement in cerebral blood flow to regions
of the brain implicated in this disorder [11, 53]. Of note, nei-
ther Pycnogenol nor the positive control, methylphenidate,
outperformed placebo on any ADHD rating scale [54]. In
summary, Pycnogenol is a promising botanical alternative in
the management of ADHD symptoms, although more studies
are required before it can be used as an ADHD treatment.
3.2. St. John’s Wort. This herb “Hypericum perforatum,”
while best known for its antidepressant qualities, was found
to have beneficial effects on other psychiatric disorders,
including obsessive compulsive disorder, major and bipolar
depression, somatization disorder, and social phobia [55]. It
has been suggested that the mechanism by which St. John’s
wort produces its therapeutic effects involves inhibition of
the reuptake of dopamine, serotonin, and norepinephrine. A
preliminary study reported improvement in ADHD symp-
toms of 3 ADHD patients (ages 14–16) given St. John’s wort
[56]. However, a more stringent randomized, double-blind,
placebo-controlled trial found that 8 weeks of St. John’s wort
treatment (300 mg/day) did not alleviate ADHD symptoms in
54 ADHD patients (aged 6–17) [32]. In light of these findings,
more studies are required to determine efficacy of St. John’s
wort in the treatment of ADHD. While the above studies did
not report adverse effects of St. John’s wort, investigations on
the safety of this treatment are still necessary.
3.3. Ginseng. Ginseng contains ginsenosides, a class of phy-
tochemicals with neuroprotective and antioxidant effects [26,
27]. Ginseng has also been reported to improve ADHD
symptoms [27]. In addition, ginsenosides are reported to
elevate levels of dopamine and norepinephrine; hence, they
could potentially be used to treat ADHD. Ginseng’s thera-
peutic benefits in ADHD were confirmed in an observational
study involving ADHD participants (18 kids, ages 6–14)
given Korean red ginseng (KRG, Panax ginseng) twice per
day for 8 weeks (1,000 mg twice daily). In this study, KRG
improved attention as measured by significant differences
in omission errors measured by the computerized ADHD-
diagnostic system (ADS) (78.56 ± 43.33 at baseline, 55.17 ±
21.44 at 8 weeks, 𝑝 < 0.023) [26]. Omission errors in
ADS measure inattentiveness. The significant decrease in
omission errors has been associated with the restoration
of impaired cognitive function in children with ADHD.
Nevertheless, the small population size limits generalizabil-
ity of the study’s findings. A large-scale study with larger
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number of participants is necessary, as well as studies
which assess long-term efficacy of KRG supplementation
[27].
Another study (randomized, double-blind, and placebo-
controlled) reported similar results in that participants
(ADHD patients aged 6–15, 𝑛 = 33), given one pouch of KRG
(1 g KRG extract/pouch) twice per day, showed improvement
in their inattention and hyperactivity scores after an 8-week
treatment course compared with the control group (𝑛 =
37) [27]. Accordingly, the KRG group displayed significantly
decreased inattention/hyperactivity scores compared with
the control group at week 8 (least squared means of the differ-
ences in inattention adjusted for baseline scores are as follows:
−2.25 versus −1.24, 𝑝 = 0.048; hyperactivity: −1.53 versus
−0.61, 𝑝 = 0.047). They also showed decreased quantitative
electroencephalography theta/beta ratio in comparison with
the control group (least squared means of the differences are
as follows: −0.94 versus −0.14, 𝑝 = 0.001). The side effect
profiles of ginseng included headache, fatigue, perspiration,
and subjective issues with the taste of the ginseng product
[26]. Ginseng’s potential use as both alternative and adjunct
ADHD treatment appears promising given the minimal
safety concerns and remarkable efficacy.
3.4. Ginkgo biloba. A unique species of tree native to East
Asia, Ginkgo biloba, has been extensively studied for its
memory-enhancing effects [25]. Currently, G. biloba is used
as an alternate treatment in patients with dementia or mem-
ory impairment [25, 49]. Studies also indicate that G. biloba
may have therapeutic benefits in ADHD. For instance, Uebel-
von Sandersleben et al. [24] reported improvement in overall
quality of life, ADHD core symptoms, and Continuous Per-
formance Test (CPT) performance in children given G. biloba
(240 mg/daily) for 3–5 weeks. A reduced dose of G. biloba
(50 mg), when combined with ginseng (200 mg) for 4 weeks
of treatment, significantly improved ADHD symptoms in a
test group of 36 children (ages 3–17) as quantified by Conners’
Parent Rating Scale-Revised (long version) (CPRS-R [L])
[24]. Accordingly, there was significant improvement in each
of the 3 areas which are most troublesome in ADHD (i.e.,
hyperactivity, cognitive problems, and oppositional behavior)
in at least 50% of the subjects given G. biloba (50 mg) and
ginseng (200 mg) up to 4 weeks after treatment. Reported
side effects of G. biloba were observed; for example, subjects
became more impulsive, hyperactive, aggressive, emotional,
and tired and manifested increased sweating [24, 25]. G.
biloba’s beneficial effects have been linked to various activities
such as improvement in cerebrovascular blood flow (allevi-
ating hyperactivity), reversal of serotonergic (5-HT) 1A and
noradrenergic receptor reductions, and inhibition of both
monoamine oxidase- (MAO-) A and MAO-B in the brain
[24, 25]. While G. biloba did produce improvement in ADHD
symptoms, a trial by Salehi et al. [25] conducted over a 6-week
period (double-blind, randomized, and placebo-controlled,
𝑛 = 50 children) found that G. biloba (80–120 mg/day)
was inferior to methylphenidate in efficacy endpoint. More
formal clinical trials are required with longer duration and
rigorous clinical endpoints in order to prove the worth of G.
biloba in ADHD treatment.
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3.5. Valerian. Valerian (Valeriana officinalis) is a perineal
plant with sedative and antispasmodic effect. It has also
been traditionally used in the treatment of insomnia, anxiety,
and restlessness [9]. The efficacy of Valerian as an ADHD
treatment has been evaluated in a double-blind, placebo-
controlled pilot study [57]. Participants (30 kids, aged 5–
11), given Valerian tincture three times a day for two weeks,
showed improvement in ADHD symptoms, in particular,
sustained inattention and impulsivity and/or hyperactivity [9,
33]. Nevertheless, the positive effects produced in the first two
weeks of the study were not maintained overall following one
week of no administration. The therapeutic effects of Valerian
have been ascribed to valerenic acid (a significant component
of Valerian) acting on the receptor gamma-aminobutyric acid
(GABA)A receptor [33]. GABA is the brain’s main inhibitory
neurotransmitter and has calming effects (for review see
[28]). Deficiency in GABA causes anxiety, restlessness, and
obsessive behavior, symptoms often seen in ADHD [58].
Valerian is considered generally safe and its use in children
with ages 3–12 years was approved by the European Scientific
Cooperative on Phytotherapy. However, Valerian must only
be used under medical supervision [9, 10, 33]. More studies
are required to augment limited clinical evidence supporting
efficacy of Valerian in treating ADHD.
3.6. Ningdong. Ningdong granule (NDG) is a widely used
Chinese medicinal preparation for various medicinal pur-
poses. NDG showed promise in treating Tourette’s syndrome,
which invited studies to determine its efficacy in ADHD [28].
A randomized, double-blind, methylphenidate-controlled
trial, where 72 children with ADHD were given 5 mg/kg/day
of NDG (𝑛 = 36) or 1 mg/kg/day methylphenidate (𝑛 =
36) for a period of 8 weeks, reported that NDG was equally
effective as methylphenidate in improving ADHD symptoms
[28]. Accordingly, no significant difference was observed
between the NDG and methylphenidate groups with regard
to the data of teacher and parent ADHD rating scales at 8
weeks after medication. Furthermore, NDG produced less
side effect profiles and was more tolerated by children as
confirmed by urine, blood, and stool analysis along with renal
and hepatic function tests. Interestingly, levels of homovanil-
lic acid (HVA), which is involved in dopamine regulation,
were increased in the sera of NDG-treated group with no
resulting change in the concentration of dopamine. Hence the
investigators proposed that NDG could be a safe, efficacious
alternative treatment for ADHD [28]. One of the limitations
of the study, however, involves the lack of placebo control
in the study and the short-term outcomes. More meaningful
pharmacological evidences to support the utility of NDG as
an ADHD treatment are also required [28].
3.7. Bacopa. Bacopa (Bacopa monnieri) is an Ayurvedic
medicine, also known as Brahmi or water hyssop. This natural
remedy has been used for centuries to modulate memory,
concentration, and learning [9]. Exploratory studies showed
that Bacopa improves memory and learning in children with
ADHD [9]. These findings were further supported by the
findings of an open-label study which showed that Bacopa
extract (225 mg/day, for 6 months) produced significant
11
improvement in ADHD symptoms of participants (31 chil-
dren, ages 6–12) [23]. In this study [29], the symptom scores
for restlessness were reduced in 93% of children, while
self-control was improved in 89% of ADHD participants.
The attention-deficit symptoms were also attenuated in 85%
of children. Moreover, learning problems, impulsivity, and
psychiatric problems symptom scores were reduced for 78%,
67%, and 52% of children, respectively. It was further reported
that 74% of the children exhibited up to a 20% reduction,
while 26% of children displayed between 21% and 50%
reduction in the total subtests scores. The efficacy of Bacopa
in this context has been attributed to its neuroprotective and
antioxidant effects, as well as regulation of dopamine, and
inhibition of cholinesterase [9, 23]. Some minor gastrointesti-
nal side effects were reported with the use of Bacopa, although
it was well tolerated by children [23]. Further studies are
warranted to confirm the safety and efficacy of this botanical
agent when used as an ADHD treatment.
3.8. Passion Flower. Passion flower is comprised of the
fragmented or cut, dried aerial parts of Passiflora incarnata
L., which is a traditional remedy for anxiety and ADHD
[29, 59]. Effect of passion flower in alleviating ADHD
symptoms was tested in 34 children with ADHD randomized
to receive tablets of Passiflora (0.04 mg/kg/day, twice daily)
or methylphenidate (1 mg/kg/day, twice daily), dosed on a
weight-adjusted basis, for 8 weeks. Both parent and teacher
rating scores revealed no significant difference in the clini-
cal benefits of Passiflora and methylphenidate treatment in
ADHD children over the course of the trial (𝐹 = 0.007, df =
1, and 𝑝 = 0.93; and 𝐹 = 0.006, df = 1, and 𝑝 = 0.94, resp.).
Moreover, side effect profile of Passiflora was less compared
with methylphenidate [59]. As the study was conducted in a
small population of patients, the results of this study need to
be validated in larger trials.
3.9. Emerging Natural Product-Derived ADHD Treatments:
Evidence from Preclinical Studies
3.9.1. Oroxylin A. Oroxylin A (5,7-dihydroxy-6-methoxyfla-
vone) is a flavonoid isolated from the root of Scutellaria
baicalensis Georgi, a herb commonly found in East Asia
[60]. Oroxylin A is an antagonist of the GABAA receptor
[60]. Furthermore, its biological activities, including antiox-
idant, anti-inflammatory, and antiallergy as well as memory-
enhancing and neuroprotective effects, provide basis for
its potential therapeutic use in ADHD. Preclinical studies
showed that Oroxylin A or its derivative (5,7-dihydroxy-
6-methoxy-4󸀠 -phenoxyflavone) produced improvement of
ADHD-like behaviors in spontaneously hypertensive rats,
animal models of ADHD [61, 62]. The therapeutic activities
of Oroxylin A have been ascribed to enhanced dopamine
neurotransmission. Ongoing studies are investigating efficacy
of Oroxylin A in ADHD patients.
3.9.2. YY162. YY162 is a combination pharmaceutical prod-
uct consisting of terpenoid-strengthened G. biloba and gin-
senoside Rg3 from ginseng. A recent study showed improve-
ment of ADHD-like symptoms, induced by Aroclor1254,
12
in mice given YY1612 [63]. The degree of alleviation of
ADHD-like symptoms induced by YY1612 was found to be
comparable to that exerted by methylphenidate. YY1612 also
produced neuroprotective effects with minimal behavioral
side effects. The mediation of the ADHD-like symptoms
in mice by YY1612 is believed to be due to its antioxidant
properties and its ability to regulate and control dopamine
and norepinephrine transporters [63]. Further studies are
required to show the potentiality of YY1612 as an ADHD
medication.
3.9.3. Sideritis scardica. The genus Sideritis plant, species
“Sideritis scardica,” has been used traditionally in the
Mediterranean region as teas and flavoring agents and
also for treatment purposes [57]. Studies have shown that
S. scardica extracts may have an inhibitory effect on the
reuptake of three key monoamines: dopamine, serotonin,
and noradrenaline [57]. Moreover, an electroencephalo-
gram (EEG) study showed that Sideritis treatment in rats
induced frequency patterns comparable to those produced
by methylphenidate [64]. Overall, these studies suggest the
benefit of Sideritis in the treatment of mental disorders,
including ADHD. Further in vivo studies measuring its
efficacy in ADHD are warranted.
3.9.4. Rhodiola. Rhodiola (Rhodiola rosea) has been shown
to stimulate CNS activity and exert adaptogenic and neu-
roprotective effects [65]. The antifatigue and antianxiety
effects of Rhodiola extract have been demonstrated in various
clinical trials [66, 67]. In view of these results, Rhodiola may
have therapeutic potential for treating anxiety disorders and
depression [68, 69]. No adverse side effects were reported in
the above-mentioned clinical trials making it a potentially
safe medication. Preclinical studies reported that Rhodiola
may enhance levels of serotonin by increasing the transport
of serotonin precursors (e.g., tryptophan and 5-HTP) [70].
Rhodiola also appears to inhibit the activity of acetyl-
cholinesterase, an enzyme which degrades acetylcholine [71].
These properties of Rhodiola demonstrate its potential as
an ADHD treatment. No trials have been conducted to test
efficacy of Rhodiola in ADHD.
3.10. Nutritional Medicines and Supplements. Previous stud-
ies showed that certain vitamins, minerals, and amino acids
may contribute to the pathology of ADHD (discussed below).
Thus, a wide range of nutritional supplements (vitamins
and minerals) have been proposed as potential adjunct and
alternative ADHD treatments. Because these agents are closer
to food substances than drugs, they do not have similar
rigorous restrictions by the Federal Drug Administration that
drugs do have and can be purchased over the counter [45].
3.10.1. Vitamins. Vitamins have been used as potential
adjuncts or alternative treatments for ADHD based on
anecdotal evidence that they produced improvement in
attentiveness and concentration in normal children [10]. As
an example, combining magnesium (6 mg/kg/day) with vita-
min B6 (0.6 mg/kg/day) during an 8-week treatment course
improved ADHD symptoms in children [45], with symptoms
Neural Plasticity
recurring again once supplementation was discontinued. The
beneficial attributes of vitamin B6 on ADHD are attributed
to its ability to influence the production of serotonin
[9, 58].
The effects of vitamin C treatment with alpha linolenic
acid- (ALA-) rich nutritional supplementation in the form
of flax oil on blood fatty acids composition and behavior
in children with ADHD were also examined [72]. This
study found that red blood cell membrane fatty acids were
significantly improved in ADHD patients receiving the above
supplementation and alleviated ADHD symptoms in ADHD
patients as evidenced by reduction of hyperactivity scores
[72]. As mentioned above, oxidative stress has been postu-
lated to play a role in ADHD [52, 73]. Thus, the antioxidant
effect of vitamin C may have contributed to the beneficial
effect of this supplementation regimen in ADHD children,
along with effects of ALA (ALA is a precursor fatty acid
and with elongation and unsaturation gets converted to
docosahexaenoic acid which is critical for normal brain
development) [73, 74].
Currently, there is another ongoing clinical study evalu-
ating the effect of tocotrienols for children with ADHD, of
which findings are not yet reported: Tocotrienols for School-
going Children With ADHD (TOCAT). Tocotrienol is a
form of vitamin E which is described to exert antioxidative
properties [74]. Moreover, aside from antioxidant properties,
tocotrienol may also inhibit phospholipase A2 enzyme which
is involved in metabolism of polyunsaturated fatty acids,
which is purportedly dysfunctional in ADHD [74, 75].
While vitamins may not directly affect symptoms of
ADHD, they have the added benefit of replenishing any
deficiencies due to poor dietary habits [10]. Nevertheless,
when initiating megadoses (i.e., 100 times the recommended
daily intake) of vitamins [76], caution must be used in
younger patients as evidence supporting efficacy of vitamins
remains to be established. Moreover, megadoses of vitamins
were sometimes detrimental at such high doses [10, 76, 77].
Further studies (randomized, double-blind, and placebo-
controlled) are necessary to validate the use of vitamins to
treat ADHD.
3.10.2. Minerals. Another proposed alternative intervention
for ADHD is mineral supplementation. Mineral deficiencies
have also been implicated in the etiology of this disorder,
making supplementation a potential means of improving
ADHD symptoms. Minerals, as cofactors, have a role in the
synthesis, uptake, and breakdown of crucial neurotransmit-
ters associated with ADHD [11, 76, 78]. Moreover, minerals
such as magnesium and calcium are necessary for aerobic
metabolism and serve as cofactors in the degradation of
blood glucose through glycogenesis, the citric acid cycle
and respiratory chain in the mitochondria. Enhanced energy
metabolism of neurons and glial cells, regulated by the mito-
chondria, is largely dependent on the presence of minerals as
well as vitamins (for review see [76]).
A 12-week double-blind study found that children sup-
plemented with zinc sulfate (150 mg) showed reduced impul-
siveness, hyperactivity, and socialization difficulties [46]. A
study by Akhondzadeh et al. [47] also reported alleviation
Neural Plasticity
of ADHD symptoms in children given zinc sulfate along
with methylphenidate therapy. The side effect profile proved
minimal, with gastrointestinal discomfort and metallic taste
being the most common. When zinc levels are low, corre-
sponding impairments in cognitive functions may ensue [11,
47]. Thus, it is believed that zinc supplementation would have
beneficial effects on cognitive functions. However, another
study showed that zinc supplementation produced negligible
beneficial effects on relieving ADHD symptoms [48]. These
opposing clinical outcomes can be attributed to genetic
factors, dosage differences, and nutritional status of patients
[11].
Iron is another well-studied mineral that has undergone
clinical trial for the treatment of ADHD. Iron is a cofactor
in the synthesis of both norepinephrine and dopamine [11,
18]. As shown in previous studies, anemic children (iron
deficient) exhibited attentional deficits [78]. A randomized,
double-blind, placebo-controlled trial found that iron supple-
mentation in children with ADHD (23 kids, ages 5–8) proved
beneficial in relieving ADHD symptoms [44]. Notably, sup-
plementation in children without iron-deficiency anemia had
inconsistent, variable results [11, 78].
Another mineral shown to improve ADHD symptoms
is magnesium. The involvement of this mineral in neuro-
transmitter synthesis supports its potentiality as an ADHD
treatment [79]. In a previous study, children supplemented
with magnesium and vitamin B6 showed improvement in
their ADHD symptoms [45].
In general, these findings indicate the worth of mineral
supplementation in ADHD. Nevertheless, a strategy sug-
gested to advance the use of minerals (as well as vitamins) in
ADHD treatment is to combine these nutrients to adequately
affect the complicated biochemical pathways that may be
defective in ADHD patients [76] and to mimic the vast array
of nutrients required for optimal brain functioning [76]. In
an open-label, on-off-on-off (reversal design) study involving
14 ADHD children (8–12 years old) treated with a 36-
ingredient micronutrient (vitamins and minerals) titrated up
to maximum dose (15 capsules/day) for 8 weeks, withdrawn
for 4 weeks and reinstated for a further 8 weeks and with-
drawn again for 4 weeks, improvement in ADHD symptoms
and mood, as well as enhanced overall functioning during
treatment phases, with deterioration in ADHD symptoms,
mood, and overall functioning during the withdrawal phases,
was observed in ADHD participants [80]. Further statistical
analyses also confirmed clinically and statistically significant
change between the intervention and withdrawal phases,
with large effect sizes observed before to after exposure of
micronutrients (𝑑 = 1.2–2.2) on ADHD symptoms during
intervention phases [80]. This study also found that 71% of
participants showed at least a 30% decrease in ADHD symp-
toms by the end of the second treatment phase, and 79% were
identified as “much improved” or “very much improved”
at the end of the second phase (5 months) based on the
clinician-rated Clinical Global Impressions (CGI) Scale when
evaluating functioning generally. The Strengths and Diffi-
culties Questionnaire (SDQ)—parent version—also revealed
that these beneficial effects of micronutrients occurred across
other areas of functioning including emotional symptoms,
13
conduct problems, and prosocial behaviors. The children’s
self-reports also verified the improvements. There was also
remarkable adherence to treatment, and side effects were
mild and transitory without safety issues after blood analysis
of participants. Indeed, a combination of different micronu-
trients may be more feasible and produce more significant
clinical benefits compared with treatment with a single
micronutrient only [76, 80].
3.10.3. Amino Acids. A number of amino acids have been
shown to exert direct or indirect effects on the levels of
specific neurotransmitters. Thus, they have the potential to
be used in treating ADHD. Amino acids, glycine, L-theanine,
L-tyrosine, taurine, acetyl-L-carnitine (ALC), GABA, 5-
hydroxytryptophan (5-HTP), and s-adenosyl-L-methionine
(SAMe), are all considered potential complementary ADHD
interventions [9, 10]. A significant portion of studies on
amino acid supplementation has focused on ALC, an amino
acid derivative. One such study (randomized, double-blind,
and placebo-controlled), utilizing ALC, reported that supple-
mentation with this protein derivative significantly reduced
symptoms of ADHD, in particular, hyperactivity and poor
social behavior, in trial participants (51 children, ages 6–
13) [34]. This effect of ALC has been attributed to mod-
ulation of neural transmission by increasing acetylcholine
synthesis, stimulating its release and release of dopamine in
the striatum in various brain regions, other than carnitine
metabolism [34]. On the other hand, a randomized, double-
blind placebo-controlled study reported conflicting findings
in that no significant effects of ALC were observed in ADHD
patients (112 children, ages 5–12) [35].
Theanine is an amino acid found in both green
and black teas [81]. This nonproteinaceous component
(n-ethylglutamic acid) has garnered increasing attention
recently due to its purported central nervous system effects.
Because of its ability to cross the blood-brain barrier, theanine
has a variety of pharmacological effects, most pertinent of
which is anxiolytic effect. These effects of theanine have been
attributed to regulation of dopamine and serotonin and an
increased production of inhibitory neurotransmitters [81].
Additionally, it has been reported that theanine produced
improvement in selective attention during the execution of
mental tasks via modulation of alpha brain wave activity.
Currently there are a handful of studies examining the
therapeutic potentials of theanine in ADHD (for review see
[81]). Theanine has also been suggested for panic disorder,
bipolar disorder, and obsessive compulsive disorder, aside
from ADHD and anxiety disorders.
3.10.4. Essential Fatty Acids. The effects of essential fatty acids
(EFAs, e.g., omega-3 and omega-6) in treating ADHD in
children have been recently investigated. Supplementation
with these fatty acids has shown modest success in controlling
ADHD symptoms [82, 83]. A study by Richardson and
Puri [36] reported that ADHD children showed improved
attention and reduced hyperactive and defiant behaviors after
supplementation with highly unsaturated fatty acids (com-
prised of eicosapentaenoic acid (EPA) 186 mg/day, docosa-
hexaenoic acid (DHA) 480 mg/day, 𝛾-linolenic acid 96 mg,
14
vitamin E 60 IU, cis-linoleic acid 864 mg, AA 42 mg, and
thyme oil 8 mg). The influence of these fatty acids on signal
transduction relevant to neuronal structure, development,
and functions may play a role in EFA-induced improvement
of ADHD symptoms [36]. Another study revealed improve-
ment in inattention and oppositional behaviors in children
who received combined EFA supplementation (polyunsat-
urated fatty acid (PUFA) supplement comprised of 480 mg
DHA, 80 mg EPA, 40 mg arachidonic acid (AA), 96 mg
gamma-linolenic acid (GLA), and 24 mg alpha-tocopheryl
acetate), although not all ADHD behaviors were alleviated
by this treatment regimen [37]. Furthermore, Sinn and Bryan
[38] reported marked improvement in ADHD symptoms in
children supplemented for 15 weeks with EFA as opposed to
those receiving placebo. The same supplementation regimen
also improved attention control and vocabulary performance
in ADHD children. Manor et al. [40] also reported improve-
ment of ADHD symptoms (impulsivity, inattention) and
mood and behavioral problems in ADHD patients given
phosphatidylserine containing omega-3, EPA, and DHA [40].
The exact mechanism by which EFAs benefit ADHD is
still unresolved but may be associated with the role of
EFAs in brain development (e.g., effects on gene expression,
neural signaling, and cellular growth and functions) [10, 37–
40, 82]. Another proposed mechanism suggests that these
therapeutic benefits may arise from increased dopaminergic
and serotonergic activity as a result of elevated EFAs [11, 40,
82].
In contrast, other studies including randomized clini-
cal trials reported no significant effects/benefits in ADHD
patients treated with EFAs compared with the placebo group
[41–43]. A meta-analysis of randomized, controlled trials
with EFAs revealed disappointing results in that most of these
trials do not support robust clinical effect of EFA supplements
as a treatment for children with ADHD [84]. Recent reviews
also reported modest benefits of EFA supplementation in
ADHD patients [85–87]. In summary, although some studies
have reported therapeutic benefits of EFA supplementation,
the current evidence for EFA as a complementary and
alternative medicine for ADHD remains controversial [86].
4. Combination Treatment Approaches:
Effects of Two Botanical Agents or When
Given with an ADHD Drug
Given the multifactorial characteristic of ADHD, the man-
agement of this disorder may benefit from a multimodal
approach. Presently, ADHD management trends are favoring
treatment of ADHD with a combination of various treatment
approaches [88, 89]. Multimodal strategies are highly attrac-
tive because they are more “holistic” and patient specific.
Moreover, combined therapies may also help improve overall
functioning by targeting symptoms of comorbid disorders
such as substance use disorder, compulsive disorders, and
learning disabilities [58].
Most multimodal treatment approaches employ the use
of stimulant medications, given their wide use in managing
ADHD, and behavioral/psychosocial therapy. A multisite
clinical trial, the Multimodal Treatment of ADHD (MTA)
Neural Plasticity
study, revealed that combination (medicinal and behavioral
treatment) and medicinal management (methylphenidate)
interventions were significantly superior to behavioral or
community care alone for managing ADHD symptoms [88].
Moreover, there was a perceived advantage of combination
treatment over single treatment (medicinal and behavioral)
for managing other functioning domains such as social skills,
academics, oppositional behavior, and anxiety/depression
[89].
In contrast, only a few studies have evaluated combi-
nation therapy utilizing nutritional/botanical supplements
with behavioral therapy or pharmacological ADHD agents
(Table 3). What is more, there are limited studies which
screened therapeutic potential of combining a botanical agent
with another plant-derived product or nutritional supple-
ments. Nevertheless, the findings of these studies have been
encouraging. Discussed below are some of these landmark
studies.
4.1. Efficacy of Combinatorial Natural Product-Derived Treat-
ment and Pharmacological ADHD Therapy. Two Chinese
medicine herbal treatments have been previously evaluated
as adjunct treatments to methylphenidate. A 2-week trial in
children randomized to receive Yizhi mixture (a combination
of 10 herbs designed to affect Yin/Yang liver functions),
methylphenidate, or combination treatment reported more
significant improvement of ADHD symptoms in children
subjected to combination treatment than in those random-
ized to either individual treatment. There were also fewer side
effects in children given Yizhi mixture alone or combination
treatment than in those assigned to the methylphenidate
group [51]. In another study, efficacy of combination therapy
with Jingling oral liquid and methylphenidate was tested [50].
This study showed that children randomized to this treatment
approach showed greater improvement in ADHD symptoms
and well as tic symptoms compared to treatment with
methylphenidate only. What deserves further investigation is
the safety profile of these herbal treatments, given alone or in
combination with methylphenidate.
In another study, Akhondzadeh et al. [47] performed
a randomized, double-blind trial to examine the poten-
tial benefits of a zinc sulfate treatment alongside methyl-
phenidate. The result showed that methylphenidate therapy
was enhanced with the addition of zinc supplementation
in participants (children, ages 5–11). Therefore, combining
botanical agents or nutritional supplements with pharmaco-
logical ADHD treatment may be a promising ADHD treat-
ment approach. As expected with combinatorial treatment
approaches, combination therapy may enhance therapeutic
efficacy or overcome therapeutic limitations of individual
treatments.
4.2. Efficacy of Combining Two Botanical Agents. The efficacy
of combining American ginseng extract, Panax quinque-
folium (200 mg), and Ginkgo biloba extracts (50 mg) to
alleviate ADHD symptoms was evaluated in 36 children
aged 3–17 years [24]. Results of this study indicated that,
after 4 weeks of treatment with this mixture, 50% of
the subjects showed improvement in each of the 3 areas
Neural Plasticity
that are most troublesome in ADHD, namely, hyperac-
tivity, cognitive problems, and oppositional behavior. The
diverse mechanisms of these agents including their abil-
ity to enhance brain functions may have been responsi-
ble for the efficacy of this combined therapy [49]. Nev-
ertheless, well-controlled trials with rigorous clinical end-
points need to be undertaken before drawing definitive
conclusions on the safety and efficacy of this treatment
approach.
5. Conclusion
There are a number of available treatment options for ADHD;
however, some of them may pose risks to patients [10].
The botanical agents discussed in this study appear to be
promising ADHD treatments considering their therapeutic
effects and negligible negative side effects. Nevertheless, it has
to be noted that ADHD is a complex disorder having multiple
causes and, thus, the use of natural product-derived treat-
ments alone may not sufficiently affect consistent change in
ADHD symptoms (see [76]). As mentioned previously, more
pronounced clinical benefit may be achieved by employing a
multimodal treatment approach such as combination therapy
of different botanical agents and/or micronutrients, botanical
agents and conventional pharmacological treatments, and
also behavioral therapy.
Although the use of natural medications for ADHD has
been considered as a “safer” approach, natural products are
still far from being called as standard ADHD treatments due
to the lack of comprehensive and appropriately controlled
clinical studies that interrogate both their efficacy and safety.
Moreover, it is challenging to compare efficacy profiles of
herb therapy with conventional pharmacological ADHD
treatments, mainly because herbal preparations are not
standardized, and question regarding their purity, reliability,
safety, and toxicity profiles will always arise [58]. Therefore,
using pure medications with known doses, described mech-
anisms of action, and adverse effects profiles is preferable
with regard to the use of natural product-derived ADHD
treatments.
The findings from recent, albeit few, studies which
evaluated efficacy of adjunct therapy of botanical agents
and nutritional supplements with a pharmacological ADHD
treatment or another botanical agent suggest that combina-
tion therapy may be a promising approach in ADHD treat-
ment. Nevertheless, positive findings from above-mentioned
studies need to be replicated, and evidence for long-term
effectiveness and safety should be aptly demonstrated. Effi-
cacy of combining other botanical agents with pharma-
cological agents including other medications aside from
methylphenidate (e.g., atomoxetine, guanfacine, and cloni-
dine) or with behavioral therapy should also be explored
in future studies. As herbs usually contain more than
one psychoactive substance and may have additive or
interactive effects with the combined treatment, the risk-
benefit balance of natural product-derived ADHD treatments
should be carefully considered when combined with other
medications.
15
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
Authors’ Contribution
James Ahn and Hyung Seok Ahn contributed equally to this
work.
Acknowledgments
This research is supported, in part, by the School of Pharmacy
of Loma Linda University (LLUSP-360034) and the Korea
Health Technology R&D Project (Grant no. A120013).
References
[1] J. M. Swanson, J. A. Sergeant, E. Taylor, E. J. S. Sonuga-Barke,
P. S. Jensen, and D. P. Cantwell, “Attention-deficit hyperactivity
disorder and hyperkinetic disorder,” The Lancet, vol. 351, no.
9100, pp. 429–433, 1998.
[2] G. Polanczyk, M. S. de Lima, B. L. Horta, J. Biederman, and L.
A. Rohde, “The worldwide prevalence of ADHD: a systematic
review and metaregression analysis,” The American Journal of
Psychiatry, vol. 164, no. 6, pp. 942–948, 2007.
[3] V. A. Harpin, “The effect of ADHD on the life of an individual,
their family, and community from preschool to adult life,”
Archives of Disease in Childhood, vol. 90, supplement 1, pp. i2–i7,
2005.
[4] S. P. Hinshaw, L. E. Arnold, and The MTA Cooperative
Group, “Attention-deficit hyperactivity disorder, multimodal
treatment, and longitudinal outcome: evidence, paradox, and
challenge,” Wiley Interdisciplinary Reviews: Cognitive Science,
vol. 6, no. 1, pp. 39–52, 2015.
[5] R. T. Brown, R. W. Amler, W. S. Freeman et al., “Treatment
of attention-deficit/hyperactivity disorder: overview of the evi-
dence,” Pediatrics, vol. 115, no. 6, pp. e749–e757, 2005.
[6] S. A. Safren, S. Sprich, M. J. Mimiaga et al., “Cognitive
behavioral therapy vs relaxation with educational support for
medication-treated adults with ADHD and persistent symp-
toms: a randomized controlled trial,” The Journal of the Ameri-
can Medical Association, vol. 304, no. 8, pp. 875–880, 2010.
[7] “ADD/ADHD treatment in children: finding treatments that
work for kids and teens,” 2015, http://www.helpguide.org/arti-
cles/add-adhd/attention-deficit-disorder-adhd-treatment-in-
children.htm.
[8] O. J. Storebø, M. Skoog, D. Damm, P. H. Thomsen, E. Simon-
sen, and C. Gluud, “Social skills training for attention deficit
hyperactivity disorder (ADHD) in children aged 5 to 18 years,”
The Cochrane Database of Systematic Reviews, vol. 12, Article ID
CD008223, 2011.
[9] J. Pellow, E. M. Solomon, and C. N. Barnard, “Complementary
and alternative medical therapies for children with attention-
deficit/hyperactivity disorder (ADHD),” Alternative Medicine
Review, vol. 16, no. 4, pp. 323–337, 2011.
[10] A. Bader and A. Adesman, “Complementary and alternative
therapies for children and adolescents with ADHD,” Current
Opinion in Pediatrics, vol. 24, no. 6, pp. 760–769, 2012.
[11] H. R. Searight, K. Robertson, T. Smith, S. Perkins, and B.
K. Searight, “Complementary and alternative therapies for
16
pediatric attention deficit hyperactivity disorder: a descriptive
review,” ISRN Psychiatry, vol. 2012, Article ID 804127, 8 pages,
2012.
[12] J. Prince, “Catecholamine dysfunction in attention-deficit/
hyperactivity disorder: an update,” Journal of Clinical Psy-
chopharmacology, vol. 28, no. 3, supplement 2, pp. S39–S45,
2008.
[13] J. Biederman, T. Spencer, and T. Wilens, “Evidence-based
pharmacotherapy for attention-deficit hyperactivity disorder,”
The International Journal of Neuropsychopharmacology, vol. 7,
no. 1, pp. 77–97, 2004.
[14] M. L. Wolraich, C. J. Wibbelsman, T. E. Brown et al., “Attention-
deficit/hyperactivity disorder among adolescents: a review of
the diagnosis, treatment, and clinical implications,” Pediatrics,
vol. 115, no. 6, pp. 1734–1746, 2005.
[15] Y. W. Wong, D.-G. Kim, and J.-Y. Lee, “Traditional oriental
herbal medicine for children and adolescents with ADHD: a
systematic review,” Evidence-Based Complementary and Alter-
native Medicine, vol. 2012, Article ID 520198, 15 pages, 2012.
[16] B. M. Rowles and R. L. Findling, “Review of pharmacother-
apy options for the treatment of attention-deficit/hyperactivity
disorder (ADHD) and ADHD-like symptoms in children and
adolescents with developmental disorders,” Developmental Dis-
abilities Research Reviews, vol. 16, no. 3, pp. 273–282, 2010.
[17] D. J. Heal, S. C. Cheetham, and S. L. Smith, “The neuropharma-
cology of ADHD drugs in vivo: insights on efficacy and safety,”
Neuropharmacology, vol. 57, no. 7-8, pp. 608–618, 2009.
[18] J. Lee, N. Grizenko, V. Bhat, S. Sengupta, A. Polotskaia, and
R. Joober, “Relation between therapeutic response and side
effects induced by methylphenidate as observed by parents
and teachers of children with ADHD,” BMC Psychiatry, vol. 11,
article 70, 2011.
[19] E. Chan, L. A. Rappaport, and K. J. Kemper, “Complementary
and alternative therapies in childhood attention and hyper-
activity problems,” Journal of Developmental and Behavioral
Pediatrics, vol. 24, no. 1, pp. 4–8, 2003.
[20] T. G. Stubberfield, J. A. Wray, and T. S. Parry, “Utilization of
alternative therapies in attention-deficit hyperactivity disorder,”
Journal of Paediatrics and Child Health, vol. 35, no. 5, pp. 450–
453, 1999.
[21] D. Sinha and D. Efron, “Complementary and alternative
medicine use in children with attention deficit hyperactivity
disorder,” Journal of Paediatrics and Child Health, vol. 41, no.
1-2, pp. 23–26, 2005.
[22] M. C. Ottolini, E. K. Hamburger, J. O. Loprieato et al., “Com-
plementary and alternative medicine use among children in the
Washington, DC area,” Ambulatory Pediatrics, vol. 1, no. 2, pp.
122–125, 2001.
[23] U. P. Dave, S. R. Dingankar, V. S. Saxena et al., “An open-label
study to elucidate the effects of standardized Bacopa monnieri
extract in the management of symptoms of attention-deficit
hyperactivity disorder in children,” Advances in Mind-Body
Medicine, vol. 28, no. 2, pp. 10–15, 2014.
[24] H. Uebel-von Sandersleben, A. Rothenberger, B. Albrecht, L. G.
Rothenberger, S. Klement, and N. Bock, “Ginkgo biloba extract
EGb 761® in children with ADHD: preliminary findings of an
open multilevel dose-finding study,” Zeitschrift fur Kinder—und
Jugendpsychiatrie und Psychotherapie, vol. 42, no. 5, pp. 337–347,
2014.
[25] B. Salehi, R. Imani, M. R. Mohammadi et al., “Ginkgo biloba for
attention-deficit/hyperactivity disorder in children and adoles-
cents: a double blind, randomized controlled trial,” Progress in
Neural Plasticity
Neuro-Psychopharmacology & Biological Psychiatry, vol. 34, no.
1, pp. 76–80, 2010.
[26] S. H. Lee, W. S. Park, and M. H. Lim, “Clinical effects of
korean red ginseng on attention deficit hyperactivity disorder
in children: an observational study,” Journal of Ginseng Research,
vol. 35, no. 2, pp. 226–234, 2011.
[27] H.-J. Ko, I. Kim, J.-B. Kim et al., “Effects of Korean red ginseng
extract on behavior in children with symptoms of inatten-
tion and hyperactivity/impulsivity: a double-blind randomized
placebo-controlled trial,” Journal of Child and Adolescent Psy-
chopharmacology, vol. 24, no. 9, pp. 501–508, 2014.
[28] J.-J. Li, Z.-W. Li, S.-Z. Wang et al., “Ningdong granule: a
complementary and alternative therapy in the treatment of
attention deficit/hyperactivity disorder,” Psychopharmacology,
vol. 216, no. 4, pp. 501–509, 2011.
[29] S. Akhondzadeh, M. R. Mohammadi, and F. Momeni, “Passi-
flora incarnata in the treatment of attention-deficit hyperactiv-
ity disorder in children and adolescents,” Therapy, vol. 2, no. 4,
pp. 609–614, 2005.
[30] J. Trebatická, S. Kopasová, Z. Hradečná et al., “Treatment of
ADHD with French maritime pine bark extract, Pycnogenol®,”
European Child & Adolescent Psychiatry, vol. 15, no. 6, pp. 329–
335, 2006.
[31] Z. Chovanová, J. Muchová, M. Sivoňová et al., “Effect of
polyphenolic extract, Pycnogenol®, on the level of 8-oxoguanine
in children suffering from attention deficit/hyperactivity disor-
der,” Free Radical Research, vol. 40, no. 9, pp. 1003–1010, 2006.
[32] W. Weber, A. Vander Stoep, R. L. McCarty, N. S. Weiss, J.
Biederman, and J. McClellan, “Hypericum perforatum (St John’s
Wort) for attention-deficit/hyperactivity disorder in children
and adolescents: a randomized controlled trial,” The Journal of
the American Medical Association, vol. 299, no. 22, pp. 2633–
2641, 2008.
[33] R. Razlog, J. Pellow, and S. J. White, “A pilot study on the efficacy
of Valeriana officinalis mother tincture and Valeriana officinalis
3X in the treatment of attention deficit hyperactivity disorder,”
Health SA Gesondheid, vol. 17, no. 1, pp. 1–7, 2012.
[34] M. G. Torrioli, S. Vernacotola, L. Peruzzi et al., “A double-
blind, parallel, multicenter comparison of L-acetylcarnitine
with placebo on the attention deficit hyperactivity disorder in
fragile X syndrome boys,” American Journal of Medical Genetics,
Part A, vol. 146, no. 7, pp. 803–812, 2008.
[35] L. E. Arnold, A. Amato, H. Bozzolo et al., “Acetyl-L-carnitine
(ALC) in attention-deficit/hyperactivity disorder: a multi-site,
placebo-controlled pilot trial,” Journal of Child and Adolescent
Psychopharmacology, vol. 17, no. 6, pp. 791–801, 2007.
[36] A. J. Richardson and B. K. Puri, “A randomized double-blind,
placebo-controlled study of the effects of supplementation with
highly unsaturated fatty acids on ADHD-related symptoms in
children with specific learning difficulties,” Progress in Neuro-
Psychopharmacology & Biological Psychiatry, vol. 26, no. 2, pp.
233–239, 2002.
[37] L. Stevens, W. Zhang, L. Peck et al., “EFA supplementation in
children with inattention, hyperactivity, and other disruptive
behaviors,” Lipids, vol. 38, no. 10, pp. 1007–1021, 2003.
[38] N. Sinn and J. Bryan, “Effect of supplementation with polyun-
saturated fatty acids and micronutrients on learning and
behavior problems associated with child ADHD,” Journal of
Developmental and Behavioral Pediatrics, vol. 28, no. 2, pp. 82–
91, 2007.
Neural Plasticity
[39] N. Sinn, J. Bryan, and C. Wilson, “Cognitive effects of polyun-
saturated fatty acids in children with attention deficit hyper-
activity disorder symptoms: a randomised controlled trial,”
Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 78,
no. 4-5, pp. 311–326, 2008.
[40] I. Manor, A. Magen, D. Keidar et al., “The effect of phos-
phatidylserine containing Omega3 fatty-acids on attention-
deficit hyperactivity disorder symptoms in children: a double-
blind placebo-controlled trial, followed by an open-label exten-
sion,” European Psychiatry, vol. 27, no. 5, pp. 335–342, 2012.
[41] R. Raz, R. L. Carasso, and S. Yehuda, “The influence of short-
chain essential fatty acids on children with attention-deficit/
hyperactivity disorder: a double-blind placebo-controlled
study,” Journal of Child and Adolescent Psychopharmacology,
vol. 19, no. 2, pp. 167–177, 2009.
[42] R. G. Voigt, A. M. Llorente, C. L. Jensen, J. K. Fraley, M.
C. Berretta, and W. C. Heird, “A randomized, double-blind,
placebo-controlled trial of docosahexaenoic acid supplementa-
tion in children with attention-deficit/hyperactivity disorder,”
The Journal of Pediatrics, vol. 139, no. 2, pp. 189–196, 2001.
[43] S. Hirayama, T. Hamazaki, and K. Terasawa, “Effect of docosa-
hexaenoic acid-containing food administration on symptoms of
attention-deficit/hyperactivity disorder—a placebo-controlled
double-blind study,” European Journal of Clinical Nutrition, vol.
58, no. 3, pp. 467–473, 2004.
[44] E. Konofal, M. Lecendreux, J. Deron et al., “Effects of iron
supplementation on attention deficit hyperactivity disorder in
children,” Pediatric Neurology, vol. 38, no. 1, pp. 20–26, 2008.
[45] M. Mousain-Bosc, M. Roche, A. Polge, D. Pradal-Prat, J. Rapin,
and J.-P. Bali, “Improvement of neurobehavioral disorders in
children supplemented with magnesium-vitamin B6. I. Atten-
tion deficit hyperactivity disorders,” Magnesium Research, vol.
19, no. 1, pp. 46–52, 2006.
[46] M. Bilici, F. Yıldırım, S. Kandil et al., “Double-blind,
placebo-controlled study of zinc sulfate in the treatment
of attention deficit hyperactivity disorder,” Progress in Neuro-
Psychopharmacology & Biological Psychiatry, vol. 28, no. 1, pp.
181–190, 2004.
[47] S. Akhondzadeh, M.-R. Mohammadi, and M. Khademi, “Zinc
sulfate as an adjunct to methylphenidate for the treatment of
attention deficit hyperactivity disorder in children: a double
blind and randomized trial [ISRCTN64132371],” BMC Psychi-
atry, vol. 4, article 9, 2004.
[48] L. E. Arnold, R. A. Disilvestro, D. Bozzolo et al., “Zinc
for attention-deficit/hyperactivity disorder: placebo-controlled
double-blind pilot trial alone and combined with ampheta-
mine,” Journal of Child and Adolescent Psychopharmacology, vol.
21, no. 1, pp. 1–19, 2011.
[49] M. R. Lyon, J. C. Cline, J. T. De Zepetnek, J. J. Shan, P. Pang,
and C. Benishin, “Effect of the herbal extract combination
Panax quinquefolium and Ginkgo biloba on attention-deficit
hyperactivity disorder: a pilot study,” Journal of Psychiatry &
Neuroscience, vol. 26, no. 3, pp. 221–228, 2001.
[50] M. J. Wang, H. Wei, and Y. Zhang, “Clinical observation of
Jingling oral liquid combined with methylphenidate in the
treatment of ADHD with transient Tic disorder,” Chinese
Traditional Patent Medicine, vol. 33, no. 9, pp. 1638–1639, 2011.
[51] G.-A. Ding, G.-H. Yu, and S.-F. Chen, “Assessment on effect of
treatment for childhood hyperkinetic syndrome by combined
therapy of yizhi mixture and ritalin,” Zhongguo Zhong Xi Yi Jie
He Za Zhi, vol. 22, no. 4, pp. 255–257, 2002.
17
[52] M. Dvořáková, M. Sivoňová, J. Trebatická et al., “The effect
of polyphenolic extract from pine bark, Pycnogenol® on the
level of glutathione in children suffering from attention deficit
hyperactivity disorder (ADHD),” Redox Report, vol. 11, no. 4, pp.
163–172, 2006.
[53] M. Dvořáková, D. Ježová, P. Blažı́ček et al., “Urinary cat-
echolamines in children with attention deficit hyperactivity
disorder (ADHD): modulation by a polyphenolic extract from
pine bark (Pycnogenol®),” Nutritional Neuroscience, vol. 10, no.
3-4, pp. 151–157, 2007.
[54] J. Sarris, J. Kean, I. Schweitzer, and J. Lake, “Complementary
medicines (herbal and nutritional products) in the treatment of
attention deficit hyperactivity disorder (ADHD): a systematic
review of the evidence,” Complementary Therapies in Medicine,
vol. 19, no. 4, pp. 216–227, 2011.
[55] J. Sarris, “St. John’s wort for the treatment of psychiatric
disorders,” The Psychiatric Clinics of North America, vol. 36, no.
1, pp. 65–71, 2013.
[56] H. Niederhofer, “St. John’s wort may improve some symptoms
of attention-deficit hyperactivity disorder,” Natural Product
Research, vol. 24, no. 3, pp. 203–205, 2010.
[57] R. Knörle, “Extracts of Sideritis scardica as triple monoamine
reuptake inhibitors,” Journal of Neural Transmission, vol. 119, no.
12, pp. 1477–1482, 2012.
[58] K. Blum, A. L. Chen, E. R. Braverman et al., “Attention-deficit-
hyperactivity disorder and reward deficiency syndrome,” The
Journal of Neuropsychiatric Disease and Treatment, vol. 4, no.
5, pp. 893–918, 2003.
[59] M. Miroddi, G. Calapai, M. Navarra, P. L. Minciullo, and S.
Gangemi, “Passiflora incarnata L.: ethnopharmacology, clinical
application, safety and evaluation of clinical trials,” Journal of
Ethnopharmacology, vol. 150, no. 3, pp. 791–804, 2013.
[60] S. Y. Yoon, I. C. dela Peña, C. Y. Shin et al., “Convulsion-related
activities of Scutellaria flavones are related to the 5,7-dihydroxyl
structures,” European Journal of Pharmacology, vol. 659, no. 2-3,
pp. 155–160, 2011.
[61] I. C. dela Peña, S. Y. Yoon, Y. Kim et al., “5,7-Dihydroxy-
6-methoxy-4󸀠 -phenoxyflavone, a derivative of oroxylin A
improves attention-deficit/hyperactivity disorder (ADHD)-like
behaviors in spontaneously hypertensive rats,” European Journal
of Pharmacology, vol. 715, no. 1–3, pp. 337–344, 2013.
[62] S. Y. Yoon, I. dela Peña, S. M. Kim et al., “Oroxylin A
improves attention deficit hyperactivity disorder-like behaviors
in the spontaneously hypertensive rat and inhibits reuptake of
dopamine in vitro,” Archives of Pharmacal Research, vol. 36, no.
1, pp. 134–140, 2013.
[63] Y. Nam, E.-J. Shin, S. W. Shin et al., “YY162 prevents ADHD-
like behavioral side effects and cytotoxicity induced by Aro-
clor1254 via interactive signaling between antioxidant potential,
BDNF/TrkB, DAT and NET,” Food and Chemical Toxicology, vol.
65, pp. 280–292, 2014.
[64] W. Dimpfel, “Pharmacological classification of herbal extracts
by means of comparison to spectral EEG signatures induced by
synthetic drugs in the freely moving rat,” Journal of Ethnophar-
macology, vol. 149, no. 2, pp. 583–589, 2013.
[65] A. Panossian, G. Wikman, and J. Sarris, “Rosenroot (Rhodiola
rosea): traditional use, chemical composition, pharmacology
and clinical efficacy,” Phytomedicine, vol. 17, no. 7, pp. 481–493,
2010.
[66] C. Ulbricht, W. Chao, S. Tanguay-Colucci et al., “Rhodiola
(Rhodiola spp.): an evidence-based systematic review by the
18 Neural Plasticity

natural standard research collaboration,” Alternative and Com- [82] M. H. Bloch and A. Qawasmi, “Omega-3 fatty acid supple-
plementary Therapies, vol. 17, no. 2, pp. 110–119, 2011. mentation for the treatment of children with attention-deficit/
[67] E. M. G. Olsson, B. von Schéele, and A. G. Panossian, “A hyperactivity disorder symptomatology: systematic review and
randomised, double-blind, placebo-controlled, parallel-group meta-analysis,” Journal of the American Academy of Child and
study of the standardised extract SHR-5 of the roots of Rhodiola Adolescent Psychiatry, vol. 50, no. 10, pp. 991–1000, 2011.
rosea in the treatment of subjects with stress-related fatigue,” [83] P. J. Sorgi, E. M. Hallowell, H. L. Hutchins, and B. Sears,
Planta Medica, vol. 75, no. 2, pp. 105–112, 2009. “Effects of an open-label pilot study with high-dose EPA/DHA
[68] A. Bystritsky, L. Kerwin, and J. D. Feusner, “A pilot study concentrates on plasma phospholipids and behavior in children
of Rhodiola rosea (Rhodax) for generalized anxiety disorder with attention deficit hyperactivity disorder,” Nutrition Journal,
(GAD),” Journal of Alternative and Complementary Medicine, vol. 6, article 16, 2007.
vol. 14, no. 2, pp. 175–180, 2008. [84] R. Raz and L. Gabis, “Essential fatty acids and attention-deficit-
[69] V. Darbinyan, G. Aslanyan, E. Amroyan, E. Gabrielyan, C. hyperactivity disorder: a systematic review,” Developmental
Malmström, and A. Panossian, “Clinical trial of Rhodiola Medicine & Child Neurology, vol. 51, no. 8, pp. 580–592, 2009.
rosea L. extract SHR-5 in the treatment of mild to moderate [85] C. M. Milte, N. Parletta, J. D. Buckley, A. M. Coates, R. M.
depression,” Nordic Journal of Psychiatry, vol. 61, no. 5, pp. 343– Young, and P. R. C. Howe, “Eicosapentaenoic and docosahex-
348, 2007. aenoic acids, cognition, and behavior in children with attention-
[70] Q. G. Chen, Y. S. Zeng, Z. Q. Qu et al., “The effects of deficit/hyperactivity disorder: a randomized controlled trial,”
Rhodiola rosea extract on 5-HT level, cell proliferation and Nutrition, vol. 28, no. 6, pp. 670–677, 2012.
quantity of neurons at cerebral hippocampus of depressive rats,” [86] D. Gillies, J. K. Sinn, S. S. Lad, M. J. Leach, and M. J.
Phytomedicine, vol. 16, no. 9, pp. 830–838, 2009. Ross, “Polyunsaturated fatty acids (PUFA) for attention deficit
[71] B. J. Hillhouse, D. S. Ming, C. J. French, and G. H. N. hyperactivity disorder (ADHD) in children and adolescents,”
Towers, “Acetylcholine esterase inhibitors in Rhodiola rosea,” Cochrane Database of Systematic Reviews, vol. 7, Article ID
Pharmaceutical Biology, vol. 42, no. 1, pp. 68–72, 2004. CD007986, 2012.
[72] K. Joshi, S. Lad, M. Kale et al., “Supplementation with flax [87] E. J. Sonuga-Barke, D. Brandeis, S. Cortese et al., “Nonphar-
oil and vitamin C improves the outcome of Attention Deficit macological interventions for ADHD: systematic review and
Hyperactivity Disorder (ADHD),” Prostaglandins Leukotrienes meta-analyses of randomized controlled trials of dietary and
and Essential Fatty Acids, vol. 74, no. 1, pp. 17–21, 2006. psychological treatments,” The American Journal of Psychiatry,
[73] N. Joseph, Y. Zhang-James, A. Perl, and S. V. Faraone, “Oxidative vol. 170, no. 3, pp. 275–289, 2013.
stress and ADHD: a meta-analysis,” Journal of Attention Disor- [88] P. S. Jensen, S. P. Hinshaw, J. M. Swanson et al., “Findings from
ders, vol. 19, no. 11, pp. 915–924, 2015. the NIMH Multimodal Treatment Study of ADHD (MTA):
[74] C. K. Sen, S. Khanna, C. Rink, and S. Roy, “Tocotrienols: the implications and applications for primary care providers,”
emerging face of natural vitamin E,” Vitamins & Hormones, vol. Journal of Developmental & Behavioral Pediatrics, vol. 22, no.
76, pp. 203–261, 2007. 1, pp. 60–73, 2001.
[75] J. R. Burgess, L. Stevens, W. Zhang, and L. Peck, “Long- [89] S. P. Hinshaw and L. E. Arnold, “Attention-deficit hyperactivity
chain polyunsaturated fatty acids in children with attention- disorder, multimodal treatment, and longitudinal outcome: evi-
deficit hyperactivity disorder,” The American Journal of Clinical dence, paradox, and challenge,” Wiley Interdisciplinary Reviews:
Nutrition, vol. 71, no. 1, supplement, pp. 327S–330S, 2000. Cognitive Science, vol. 6, no. 1, pp. 39–52, 2015.
[76] J. J. Rucklidge and B. J. Kaplan, “Broad-spectrum micronutrient
treatment for attention-deficit/hyperactivity disorder: rationale
and evidence to date,” CNS Drugs, vol. 28, no. 9, pp. 775–785,
2014.
[77] L. E. Arnold, “Treatment alternatives for Attention-Deficit/
Hyperactivity Disorder (ADHD),” The Journal of Attention
Disorders, vol. 3, no. 1, pp. 30–48, 1999.
[78] J. J. Rucklidge, J. Johnstone, and B. J. Kaplan, “Nutrient sup-
plementation approaches in the treatment of ADHD,” Expert
Review of Neurotherapeutics, vol. 9, no. 4, pp. 461–476, 2009.
[79] B. Starobrat-Hermelin and T. Kozielec, “The effects of magne-
sium physiological supplementation on hyperactivity in chil-
dren with Attention Deficit Hyperactivity Disorder (ADHD).
Positive response to magnesium oral loading test,” Magnesium
Research, vol. 10, no. 2, pp. 149–156, 1997.
[80] H. A. Gordon, J. J. Rucklidge, N. M. Blampied, and J. M.
Johnstone, “Clinically significant symptom reduction in chil-
dren with attention-deficit/hyperactivity disorder treated with
micronutrients: an open-label reversal design study,” Journal of
Child and Adolescent Psychopharmacology, vol. 25, no. 10, pp.
783–798, 2015.
[81] A. L. Lardner, “Neurobiological effects of the green tea con-
stituent theanine and its potential role in the treatment of
psychiatric and neurodegenerative disorders,” Nutritional Neu-
roscience, vol. 17, no. 4, pp. 145–155, 2014.